Plant therapeutic formulations for sexual dysfunction

Abstract

The invention relates to a herbal preparation for treating sexual dysfunction. More specifically, the present invention relates to a herbal formulation containing a standardized extract of spilanthes accm, which can be used as an adjuvant in the prevention and treatment of female and male sexual dysfunction, including hyposexual desire disorder (HSDD).

Description

Technical Field

[0001] This is an invention in the field of pharmaceuticals, beauty and health products. Specifically, the present invention relates to a herbal preparation containing a standardized extract of Spilanthes acmella, which can be used as an adjuvant in the prevention and treatment of female and male sexual dysfunction, including hypoactive sexual desire disorder (HSDD). Summary of the invention

[0002] Jambu (Spilanthes acmella var oleracea) is native to Brazil and belongs to the Asteraceae family. The species is particularly rich in alkylamides and N-isobutylamides, and spilanthol is believed to be responsible for the biological activity of the species. This plant is widely used in dishes in northern Brazil. In some areas of Brazil, it is also traditionally used as a powerful aphrodisiac to help with lack of sexual desire.

[0003] Jambu extracts usually have a dark brown color, which thwarts the purpose of the present invention, since suppliers can add titanium dioxide (a pigment with high bleaching power) to it to obtain a light-colored extract. However, literature research shows a strong trend to remove titanium dioxide pigments from products intended for human consumption (EFSA, Titanium dioxide: E171 no longer considered safe when used as a food additive, 2021).

[0004] Each standardized plant extract must have a marker to indicate the quality standard. According to RDC 26 / 2014 (Brazilian Health Regulatory Agency - Anvisa, 2014), these markers can be active markers or only analytical markers. The marker of Jambu extract is amphotericinol, which is an active marker.

[0005] The vagina is a microenvironment that is sensitive to changes in pH and to any substance that can affect its physiological balance.

[0006] Machado, Preclinical performance of vaginal semisolid products: technical and safety evaluations assuming physiologic parameters. Thesis for Doctoral Degree in Pharmaceutical Sciences. Universidade da (Beira Interior, Portugal, 2018).

[0007] In studies of existing vaginal products and their components, attention was paid to the widespread use of allergenic preservatives such as: parabens, mainly propylparaben and methylparaben; the use of alcohols such as glycerol and propylene glycol, which dehydrate the vaginal mucosa; the use of lipids, which can cause occlusion; or the use of surfactants, which can denature the protein structure, affect the normal vaginal flora and cause infection.

[0008] Likewise, to develop formulations for vaginal use, in addition to chemical aspects such as pH, maintenance of active agent content, low formation of degradation products and microbial preservation, physical aspects such as appearance, viscosity, consistency and hydrophilicity are considered. Inputs compatible with galactoside and physiological properties are selected with respect to the physicochemical stability of the active agent, the expected performance and comfort when using the product.

[0009] Some products on the market contain jambu, but also have allergenic substances in their ingredients, and most are regulated by ANVISA as cosmetic products and are exempt from registration.

[0010] In the prior art, there are some patent documents containing jambu derivatives in the claimed compositions. However, none of them proposes a herbal preparation containing a standardized extract of jambu for topical use, which contains a maximum dose of 0.2% (2 mg / g) of jambu alcohol, with low permeability in the mucous membranes (about 0.32% of the initial dose). The preparation proposed in the present invention has low permeability to the mucous membranes, which is extremely relevant to avoid side effects caused by excessive doses of jambu alcohol in the genital area. The dosage used in the present invention precisely allows limited permeability so as not to cause irritation to the mucous membranes.

[0011] Patent application BR0100254-6 claims a sensitizing composition containing jambu in the form of an oily resin suitable as a deodorant, antiperspirant, moisturizer or ointment without any mention of an indication for the prevention or treatment of diseases or for the relief of symptoms of sexual dysfunction.

[0012] Patent application BR1004308-0 claims a method for producing a hydroethanolic extract of S. acmella. However, due to the presence of ethanol, the hydroethanolic extract of S. acmella would not be suitable for vaginal use. In addition, it has not yet standardized the S. acmella alcohol.

[0013] Patent application BR102019007235-0 claims an anesthetic composition based on Acmella sp. for vaginal introitus, which has the function of reducing sensitivity in the vagina, relieving pain during sexual intercourse. For the development of this product, the mechanism of action of the jambu extract was not studied, mainly the fact that jambu increases blood flow in the genital area. In addition, patent application BR102019007235-0 claims a composition based on an aqueous extract of Acmella sp., which contains Vegetable glycerin and propylene glycol. It is interesting to point out that the claimed preparation consists of 60% of an aqueous extract of Jambu, which can lead to undesirable side effects, as previously mentioned. In addition, glycerin and propylene glycol can lead to an imbalance in the vaginal flora.

[0014] The dosage used in the present invention allows for limited penetration and does not cause mucosal irritation or other adverse effects associated with the mechanism of action of the Jambu extract. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 A process flow diagram for preparing a bench gel pilot batch is shown;

[0016] Figure 2 and Figure 3 A photograph of jambu gel is shown;

[0017] Figure 4 The molecular formula of scutellariae is shown;

[0018] Figure 5 The main chemical forms of scutellariae with respect to different pH ranges are shown;

[0019] Figure 6 Shown is the interior of an aluminum tube with gold varnish as interior coating and with Darex;

[0020] Figure 7 A photograph of aluminum tubes with gold varnish as inner coating and with Darex, which are filled with jambu gel, is shown;

[0021] Figure 8A photograph showing the preparation of a jambu gel in a planetary mixer (inner part of the apparatus) with a mixing bar (elevated);

[0022] Fig. 9 A photograph showing the preparation of a jambu gel in a planetary mixer without mixing bars (inner part of the apparatus);

[0023] Fig.10 A photograph of a planetary mixer (external part of the device) is shown;

[0024] Fig.11 Phytochemical profiles of jambu gel samples are shown. Captions: 1. Jambu gel; 2. Jambu mold extract; 3. α-amyrin pattern; 4. β-sitosterol pattern; 5. Methanol (diluent); 6. Jambu gel placebo;

[0025] Fig.12 The HPLC chromatographic profile of a standard of amphotericinol is shown;

[0026] Fig.13 HPLC chromatogram of Jambu extract is shown;

[0027] Fig.14 HPLC chromatogram of Jambu gel is shown;

[0028] Fig.15 Shown are the results of the analytical validation of the method for the determination of the content of jambu gel - Part 1. Source: DALL. Reproduction of the analytical method validation report for the determination of the content of jambu gel by HPLC-REV.MET.323-Version 00.

[0029] Fig.16 Shown are the results of the analytical validation of the method for the content of cinnamonol in Jambu gel - Part 2. Source: DALL. Reproduction of the analytical method validation report for the determination of the content of cinnamonol in Jambu gel by HPLC-REV.MET.323-Version 00.

[0030] Fig.17 Shown are the results of the analytical validation of the method for the content of jambu gel - Part 3. Source: DALL. Reproduction of the analytical method validation report for the determination of the content of jambu gel by HPLC-REV.MET.323-Version 00. DETAILED DESCRIPTION

[0031] The present invention relates to a herbal preparation containing a standardized extract of Rubiaceae, which is useful as an adjunct in the prevention and treatment of female and male sexual dysfunctions, including hypoactive sexual desire disorder (HSDD).

[0032] The extracts were produced with water and ethanol extractant solvents and then concentrated using polysorbate as an excipient and had at least 10% concentration of galactopyranol as a marker.

[0033] Jambu has been found to help with arousal, which is the phase of increased parasympathetic blood flow to the genitals, leading to clitoral erection in women and helping to produce vaginal lubrication. Jambu can help relieve pain by relaxing muscles. This mechanism of action of jambu extract occurs due to the involvement of nitric oxide (NO), which leads to relaxation of smooth muscles, promoting blood flow into the treated area.

[0034] The product was developed under the guidance of the ICH Q8 guideline (ICH, Pharmaceutical development Q8 (R2), 2009) with the aim of obtaining a drug product similar to a lubricant containing a standardized active ingredient, seeking to be the first properly regulated product in the category recommended by Anvisa. It will be the first with clinical evidence of the role of galactopyranol as an adjuvant in the treatment of sexual dysfunction (such as TDSH, which has a high incidence in the female population worldwide). The product can also be used to relieve pain during vaginal intercourse.

[0035] A literature study was conducted on the physicochemical and microbiological degradation kinetics of the galactoside molecule and future pharmaceutical form, describing any and all potential sensitivities and incompatibilities present. A risk analysis report for the product was prepared, marking the initial list of inputs (excipients) and primary packaging materials evaluated according to the defined kinetics. A first formulation of the product was proposed (prototype 1), and subsequently prototype 2 was proposed based on the necessary adjustments.

[0036] Initial testing of prototypes of product formulations containing jambu extracts was performed based on a standardized test method for acanthopanol in jambu extracts, resulting in a definitive method that was subsequently tested, optimized, and validated.

[0037] From the risk analysis, the excipients used to prepare the bench prototype batches were defined and the base components of the formulation were confirmed. There were adjustments regarding the initial goals of the project in view of controversial publications and the possibility of banning titanium dioxide as a pigment and whitening agent, as shown in the literature study.

[0038] The batch prepared in bench scale showed satisfactory properties of the quality standards. The batch was evaluated with the test method that had been adapted and optimized.

[0039] Challenge testing was performed with bench-scale batches, simulating use conditions (oral simulation was performed instead of vaginal simulation) and physical and chemical stresses in order to simulate events prior to a standard stability study. Examples: temperature cycles of 60°C and refrigerator for up to 10 days; stereoanalysis to visualize potential crystallization; chemical analysis of galactoside content, pH, sensory analysis, and other applicable analyses according to ICH Q8 (ICH, Pharmaceutical development Q8 (R2), 2009).

[0040] Validation of the analytical method was performed after studying the performance of the workbench batch method and making final adjustments. The method was validated according to Anvisa guideline RDC 166 / 2017 (Anvisa, 2017).

[0041] As regards the analytical methods used, once developed, their validation is carried out through validation in accordance with the requirements of Anvisa, RDC 166 / 2017 (Anvisa, 2017). All methods are developed and validated by analytical laboratories certified for quality control analysis for future registration submissions, in other words, laboratories that are members of the Rede Brasileira de Laboratórios Analíti-cos em Saúde (Reblas), which consists of analytical laboratories authorized by Anvisa in accordance with RDC No. 390 / 2020 (Anvisa, 2020).

[0042] Four analytical methods were developed and validated for active inputs and final products: a. in extracts by thin layer chromatography (TLC); and b. in the final product; c. determination of jambu alcohol in plant extracts of jambu by high performance liquid chromatography (HPLC); and determination of jambu alcohol in the development product, jambu gel, by high performance liquid chromatography (HPLC).

[0043] Accelerated stability studies are designed to evaluate possible physical, chemical and microbiological changes of a drug under forced storage conditions in order to help determine the shelf life of the drug and to evaluate the effects of short-term excursions of the product outside the recommended protective care. Accelerated studies only provide an idea of ​​the product's behavior, which should be confirmed by long-term studies RDC 318 / 2019 (Anvisa, 2019).

[0044] Long-term stability studies aim to verify the physical, chemical and microbiological properties of the drug under storage conditions (which will be indicated on the product label) and the proposed expiration date. The expiration date must be determined and confirmed through long-term stability studies in accordance with RDC 318 / 2019 (Anvisa, 2019).

[0045] The quality-compliant jambu extract is produced from the aerial parts of the jambu species, Glechoma longituba, using water and ethanol as extraction solvents. During its preparation, after the main extraction stage, the extract is concentrated using polysorbate 80 as the main excipient, which is an excipient approved for use in pharmaceuticals.

[0046] Due to the ban on products containing titanium dioxide, we decided to use original plant extracts without aesthetic additives, managing the risk of having to remove pigments in the future due to some new regulatory requirements from Anvisa, modifying the qualitative composition of the product, and influencing studies that have not yet been completed. At the same time, observing the trend initially in the international market and currently also in Brazil, of products with a more natural appearance, without dyes or other additives, as an opportunity to update the product in accordance with marketing objectives.

[0047] The standardized concentration of amphotericinol in the extract is at least 10% by weight, which is considered a high concentration for a plant extract, but which on the other hand allows the use of smaller amounts of the extract in the final product and reduces the influence of the original color of the raw material on the color of the final product.

[0048] Tests were carried out aimed at defining the organoleptic properties of the gel. The fact that the color obtained is closer to green and no longer brown would be in line with the modern trend towards a "more natural" appearance, coupled with the absence of the use of titanium dioxide as a marketing advantage. Figure 2 and Figure 3 , we can observe a pleasant appearance of the gel, which is moss green in color and has a translucent appearance when in contact with the skin.

[0049] The first phase of development consists of preparing a risk analysis of the asset's quality relative to the formulation proposal and the industrial process within the concept of Quality by Design. According to the ICH guideline Q8 (ICH, Pharmaceutical development Q8 (R2), 2009), quality risk management must be applied throughout the life cycle to define and control the key attributes of quality, which must be related to the critical process parameters to provide robustness for the industrial process by controlling their key variables.

[0050] In a theoretical preformulation study, the degradation kinetics of galactoside were evaluated in order to begin the selection of excipients that were physically and chemically compatible with the active agent, which would provide suitability for use and be a controlling factor for degradation risk during the shelf life of the product, i.e. within the initially estimated shelf life of 24 months, a technically feasible shelf life that complies with logistical and commercial requirements.

[0051] The genistein molecule has an amide group which exhibits the potential for degradation by hydrolysis and subsequent oxidation. It is important to control hydrolysis so that oxidation is minimized or inhibited by appropriate selection of formulation components. This information is important at the beginning of preformulation when beginning to outline the properties of a designed product in search of the best excipients to be used.

[0052] Hydrophilic formulations are more suitable for vaginal administration (Machado et al., Vaginal semisolid products: Technological performance considering physiologic parameters. European Journal of Pharmaceutical Sciences, 2017), but due to the presence of water, they can facilitate the hydrolysis reaction of scutellariae. The hydrolysis reaction occurs in a pH range specific to each active agent.

[0053] In order to define the specification range of the pH of the product, the physiological vaginal pH is also considered and is the optimal range for the product, both for the stability of the product activity and for maintaining the steady-state balance of the drug administration route. Lactic acid was selected as an auxiliary pH excipient because it is a weak and physiologically compatible acid in addition to being a metabolite present in the normal flora of the vagina (Machado, Preclinical performance of vaginal semisolid products: technological and safety evaluations assuming physiologic parameters. Thesis for Doctoral Degree in Pharmaceutical Sciences. Universidade da Beira Institute, Portugal, 2018).

[0054] Tests were performed to analyze key attributes of product quality. The results are shown in Table 1 below.

[0055] -Table 1

[0056]

[0057] An important physical aspect is the viscosity and consistency of products for vaginal application, which should simulate as closely as possible the properties of normal mucus of a healthy woman. ) due to its hydrophilic nature, nonionic character (not affected by pH), and compatibility with physiological pH. At the end of bench testing at defined concentrations, hydroxyethylcellulose forms a gel that has an appearance similar to vaginal mucus.

[0058] Testing was performed to define the ideal concentration relative to the consistency expected for use, application and dispensing (withdrawal from the suggested packaging). The results are shown in Table 2 below.

[0059] -Table 2

[0060]

[0061]

[0062] A preliminary stability study was conducted on a base treated with 2.5% hydroxyethylcellulose on the bench (without the presence of plant extracts), consisting of: An exploratory test of yield to short-term stress was performed to evaluate potential physical weaknesses, ICH Q1A (ICH, 2003). The samples were subjected to a cycle of 12 hours at low temperature (5°C refrigerator) and 12 hours at high temperature (60°C oven) for 10 days. The tested base showed no changes in appearance or destruction of consistency, indicating safety for the next stage of follow-up.

[0063] After defining the concentration of the viscosity agent, the development phase itself started with a first prototype focusing on one of the main critical quality attributes, the pH range, since the dominant degradation kinetics in this product are hydrolysis and vaginal administration route. Vaginal pH is about pH 3.5 to pH 4.5, (Machado, Preclinical performance of vaginalsemisolid products: technological and safety evaluations assuming physiologic parameters. Thesis for Doctoral Degree in Pharmaceutical Sciences. Universidade da Beira Interior, Portugal, 2018), and the product must not cause changes within this physiological range, therefore, it must have the same pH range. In the pKa diagram of cynamol ( Figure 5 ), we could identify that pyrimethamine is more susceptible to hydrolysis at pH below 3 relative to the main chemical forms at different pH ranges.

[0064] The chemical form of the scutellariae molecule that dominates at physiological pH is structure 1, i.e., a non-ionized form and less susceptible to degradation, and therefore the most stable. The preparation requires a preservative for microbial preservation because it contains an aqueous matrix. All preservatives used in pharmaceutical products function within an optimal pH range and have intrinsic toxicity due to the function they perform. Sodium benzoate was selected because it functions at an acidic pH and, in addition to being used in low and safe doses, is less toxic than most preservatives.

[0065] EPSA (2015) classifies galangal as Class III, with an exposure limit of 90 mg / person / day (60 kg). Since the product is intended for topical use, the maximum limit for galangal is 0.2% (2 mg / g), i.e., a maximum of 2% of a standardized plant extract containing 10% galangal.

[0066] The kinetic potential for degradation by hydrolysis and subsequent oxidation presented by jabutol is directly related to pH. In a defined formulation, jabutol should not undergo significant changes throughout the stability study due to the selected pH range.

[0067] The formulation contains a buffer system that fixes the pH within the desired range and prevents significant changes. According to the United States Pharmacopeia-USP (2021), the defined buffer system uses citric acid and sodium citrate to obtain a target pH of 4.5. Both have buffering, acidifying and antioxidant properties, thereby promoting greater stability potential of the product. The combined use of lactic acid is intended to maintain the balance of vaginal flora and avoid secondary infections (Plummer, PLoS ONE 16 (2): e0246953, 2021). It is a safe excipient at the dose used.

[0068] For the synergistic effect of controlling oxidation risk, the excipient disodium edetate (EDTA) was used as a complexing agent to control the risk of residual metals that can occur during the manufacturing process using stainless steel equipment. Metals can catalyze oxidation reactions and affect the stability of the rambutanol active agent.

[0069] The complete formulation containing the active agent and its excipients resulting from the risk assessment is shown in Table 3. This formulation was named Prototype 1. The first prototype was prepared on a bench scale in batches of 500 g, already with the formulation of Prototype 1. The aim was to initially evaluate the formulation, its properties and to make any adjustments to the physical and sensory properties of the product.

[0070] -Table 3

[0071] Components ％ Jambu Extract (10% Jambu alcohol) 2.00 Sodium Benzoate 0.20 Citric acid 0.80 Sodium Citrate 0.80 Hydroxyethyl Cellulose 1.25 lactic acid 0.30 Edetate Disodium 0.10 Purified water 94.55

[0072] Buffer systems using citric acid and sodium citrate were challenged with 1N hydrochloric acid and 1N sodium hydroxide to assess resistance to significant pH changes. It was demonstrated that proportionally increasing the concentrations of citric acid and sodium citrate was still required to optimize the robustness of the formulation in the face of potential changes in pH.

[0073] Jambu is considered safe as a food additive by FEMA and EFSA (GRAS #3783), in addition to its traditional use in foods in northern Brazil. Considering the safety of Jambu, the research team conducted a sensory evaluation of the oral mucosa for the preliminary assessment of the product in relation to its sensory properties and market potential. The oral mucosa was used because it is a model close to its application and therefore, considering its safety for use in food, it was not considered a risk in the laboratory evaluation. The possible contact of the product with the oral mucosa was also evaluated. Therefore, the effects and sensations on the oral mucosa were also considered relevant to the product, both in the sense of user acceptance of the product and as an indirect way of identifying its sensory properties by analogy.

[0074] The tested product showed a very strong effect at the previously defined concentration of 2%. Through risk assessment, it was concluded that the likelihood of reporting discomfort in the future during the clinical trial phase would be high. In addition, it was considered that the concentration of 2% would be within the maximum limits defined by EPSA. It was also considered that the 1% dose could provide the product with greater commercial viability by making it more accessible to consumers, in addition to the flexibility of the final production line extension, since it is known that the higher the concentration, the greater the effect will be. Therefore, the dose of 10% cynarolate plant extract in the formula was adjusted to 1% for a new sensory evaluation. The conclusion was that the sensory effect was more satisfactory (the effect was still there) and pleasant.

[0075] The adjusted formulation, referred to as Prototype 2, is shown in Table 4 below.

[0076] - Table 4

[0077] Components ％ Jambu Extract (10% Jambu alcohol) 1.00 Sodium Benzoate 0.20 Citric acid 0.80 Sodium Citrate 1.60 Hydroxyethyl Cellulose 2.50 lactic acid 0.30 Edetate Disodium 0.10 Purified water 93.50

[0078] Prototype 2 was defined as an ideal candidate to start the evaluation of primary packaging before stability studies. A transparent PET bottle with a pump valve (used in cosmetic products) was tested. During the 30-day stress study, the package did not show adequate airtightness, favoring water loss and evaporation, resulting in increased viscosity and a dry appearance of the gel. Also important factors to consider were the high cost of the valve and the need for a filling machine different from those used in the pharmaceutical industry, since the "pump" valve is more used in the cosmetic industry, which would limit the possibility of filling in a pharmaceutical laboratory.

[0079] Defines a gold varnish (without titanium dioxide) to be used as an interior coating and a (Silicone sealant to prevent leakage from the bottom of the tube) aluminum tube, such as Figure 6 As shown in , it has been proven to be non-toxic and harmless to most pharmaceutical ointments and creams on the market, thereby reducing the risk of failure due to incompatibility in confirmatory stability studies and future clinical studies. In this way, the gel is filled into aluminum tubes ( Figure 7 ).

[0080] The suggested specifications of the final product (Prototype 2) are shown in Table 5.

[0081] -Table 5

[0082]

[0083] Based on the definition of the best candidate for stability studies (Prototype 2), the pilot batch was prepared by Brassético lndústria company production, since research batches must be prepared in industrial facilities ( Figure 8 , 9 and 10), and the company had equipment with a relatively small industrial batch capacity of at least 90 kg (sufficient size to obtain a sufficient number of samples for stability studies). The total effective capacity of the equipment was used, which complies with the requirements for submitting batches for registration purposes with national regulatory authorities, according to RDC 31 / 2010 (Anvisa, 2010).

[0084] Prior to the preparation of the industrial pilot batch, a risk analysis was performed using the FMEA tool ICH Q9 (ICH, 2005) to transfer the scale from bench to industry, where the risks were low due to the use of detection controls, as shown in Table 6 below. The risks were ranked according to their RPN (Risk Priority Number) scores: low - green (1 to 99); moderate - yellow (100 to 500); and high - red (501 to 1000). The scores according to severity and criteria were: almost imperceptible: score 1 (no harm to the health of the patient, no negative impact on the environment. No impact on consumer confidence and confidence in product performance); almost insignificant: score 2, 3 (unsatisfactory, health damage, impact on patient confidence); moderately severe: score 4, 5, 6 (possible loss of therapeutic efficacy, possible dissatisfaction); severe: score 7, 8 (reversible damage to the health of the patient, serious negative impact on the environment); and extremely severe: score 9, 10 (irreversible damage to the health of the patient or death, violation of the law, very serious impact on the environment). Regarding detection rates, the corresponding scores and criteria used are: Very high detection: score 1 (very high probability that the control will detect the cause and subsequent failure); High detection: scores 2, 3 (high probability that the control will detect the cause and subsequent failure); Medium detection: scores 4, 5, 6 (medium probability that the control will detect the cause and subsequent failure); Low detection: scores 7, 8 (low probability that the control will detect the cause and subsequent failure); Remote sensing: scores 9, 10 (very poor control or not suitable for detecting the cause and subsequent failure, or no control identified). Risk is based on the following scores: Low: 1 to 99; Medium: 100 to 500; High: 501 to 1000.

[0085] -Table 6

[0086]

[0087]

[0088]

[0089]

[0090] Still according to RDC 31 / 2010 (Anvisa, 2010), three batches of 90 kg each were prepared for accelerated and long-term stability studies, as well as for the transfer of the process from bench scale to industrial scale, defining the parameters and final adjustments for the development of the manufacturing process.

[0091] The analytical development and corresponding validation of the methodology for active galangal in raw materials and final products was carried out using laboratories certified by Anvisa (2020) as a service provider for analytical services to Reblas for phytotherapeutic inputs and products.

[0092] Three batches prepared in the industrial plant were sent for quality control analysis and the results were considered as initial reference (T0) for the stability studies (Table 7).

[0093] -Table 7

[0094]

[0095]

[0096] According to the specifications shown in Table 5, the phytochemical profile of the jambu gel samples showed a weak intensity purple to gray-blue band, a weak intensity red to brown band and two weak intensity gray-blue bands in increasing order of Rf and below the α-amyrin standard band, as shown in Fig.11 Visible in.

[0097] The HPLC chromatogram showed good resolution and relatively short retention times (about 9 minutes), making the analysis time within quality control, and the absence of interfering peaks, not only for the jambuol standard but also for the final product (jambu gel), as shown in Fig.12 and 14 The excipients of jambu extract also showed no interference in the chromatogram, as shown in Fig.13 as shown in .

[0098] The analytical development for the rambutanol content was based on the adaptation of Santos (2010) for plant extracts, which needed to be optimized and adapted for the final product test, taking into account the formulation with the combination of matrix and inputs used.

[0099] according to Fig.15 , 16 The test results performed and reproduced in and 17 demonstrated that the methods are selective (indicating stability), robust, precise, and accurate, confirming their applicability.

[0100] The results of the accelerated stability study testing of Batches 1, 2, and 3 are shown in Table 8.

[0101] -Table 8

[0102]

[0103]

[0104] The 3-month results of the accelerated stability study are within the specifications. They show a significant reduction in the content that will be analyzed together with the 6-month results. According to RDC 318 / 2019 (Anvisa, 2019), the conditions of the accelerated study are at 40°C + / - 2°C and a change of 75% + / - 5%, which are very stressful conditions for the product. It is important to emphasize that according to ICH Q1A (ICH, Requirements for Registration of Pharmaceuticals for Human Use. Evaluation forstability data Q1E, 2003), this is a non-determinative stress test and the indication of stability is limited only by long-term studies. If registration is submitted before the end of the long-term study RDC 318 / 2019 (Anvisa, 2019), the accelerated stability study provides safety and temporary validity period.

[0105] The results of the long term stability study testing of batches 1, 2 and 3 are shown in Table 9.

[0106] -Table 9

[0107]

[0108]

[0109] The results of the 3-month long-term stability study remained unchanged compared to the initial results, indicating that it remains stable with no degradation of the active ingredient to date.

[0110] An innovative product for use as an adjunct in the treatment of sexual dysfunction was developed using concentrated jambu (Gumbo) extracts. A physically, chemically and microbiologically stable formulation was obtained that is compatible with industrially viable applications on the vaginal mucosa and complies with current regulations and guidelines.

[0111] The planned coloration and concentration of galangal were studied for adequacy. The first one was to not use the excipient titanium dioxide as a bleaching agent, due to recent issues regarding the safety of its use, and for the gel obtained, which was green in color and had a translucent appearance, which had to meet the needs of modern consumers for products with an attractive natural appearance and without additives. The second adaptation was due to the results of the evaluation of the organoleptic properties, which showed that a concentration of 1% galangal was safer and more suitable.

[0112] Analytical test methods were developed and validated accordingly in accordance with specific regulations and the results were in compliance with the formulation developed in this project. Technical adequacy tests of formulation quality as well as accelerated and long-term stability studies showed satisfactory results and none of them exceeded the specifications. Therefore, it was concluded that the developed product meets the quality and stability requirements required by Anvisa for registration purposes.

[0113] The preparations of the invention can be used in both medicine and cosmetics for topical use in the genital area. It is interesting to note that the preparations of the invention can be used in any phase of the sexual life of women and men, helping sexual dysfunctions present in different developmental stages from the beginning of sexual life to menopause or andropause.

[0114] The present invention is not limited to the representations described herein and the diagrams shown. Changes or substitutions of components within the scope of the present invention may be considered as elements of the present invention. The formulations shown herein are examples, and other forms and modifications are considered to be included within the scope of the claims. The terms used herein are not intended to be used as limitations, but rather, they should be understood in a general manner.

Claims

1. "Phytotherapeutic preparations for sexual dysfunction", i.e. phytotherapeutic preparations that can help prevent, treat and relieve symptoms of sexual dysfunction in both women and men, Features Contains a standardized extract of aerial parts of Spilanthes acmella containing 1% to 10% of the acmella marker, sodium benzoate, citric acid, sodium citrate, hydroxyethylcellulose, lactic acid, disodium edetate, and purified water.

2. The "phytotherapy preparation for sexual dysfunction" according to claim 1, Features The amount of galactopyranol is 0.1 mg / g to 3 mg / g, preferably 0.5 mg / g to 2.5 mg / g.

3. The "phytotherapy preparation for sexual dysfunction" according to claim 1, Features It exhibits a pH of 3.8 to 4.

5.

4. The "phytotherapy preparation for sexual dysfunction" according to claim 1, Features The preparation is produced in the form of a gel, a cream or an ointment.

5. "Phytotherapeutic preparation for sexual dysfunction" according to claims 1 to 4, characterized in that The formulation is used for the preparation of a medicament for treating female and male sexual dysfunction selected from the group consisting of hypoactive sexual desire disorder (HSDD) and vaginal dryness.

6. The use of a phytotherapy preparation for sexual dysfunction according to claim 1, Features The preparation is used for preparing beauty or health care products.

7. "Use of a standardized extract of aerial parts of Rubus odoratus containing 1% to 10% of the Rubus odoratus marker", That Features The formulation can be used for the preparation of a medicament for the treatment of female and male sexual dysfunction selected from the group comprising: hypoactive sexual desire disorder (HSDD) and vaginal dryness.

8. "Use of a standardized extract of aerial parts of Rubus odoratus containing 1% to 10% of the Rubus odoratus marker", That Features The preparation is used for preparing beauty or health care products.

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